Peptide toxins that selectively target insect Na_Vand Ca_Vchannels

Abstract

Numerous metazoans express venoms for the purpose of defense, competitor deterrence or prey capture. Peptide neurotoxins are particularly well represented in the venoms of arachnids, cnidarians and mollusks and these toxins often possess high affinity and specificity for particular classes of ion channels. Some of these toxins have become the defining pharmacology for certain vertebrate ion channel subtypes. Unfortunately, due to differences in the structure, pharmacology and ion selectivity of insect voltage-gated sodium (Na V ) and calcium (Ca V ) channels compared with their vertebrate counterparts, these peptide toxins have proven less useful for the characterization of insect ion channels. Despite these disparities in channel structure and function, the armament of peptide toxins that specifically modulate the activity of insect ion channels is slowly expanding.

Analysis of the Structural and Molecular Basis of Voltage-sensitive Sodium Channel Inhibition by the Spider Toxin Huwentoxin-IV (μ-TRTX-Hh2a)

“…These observations underscore the importance of Trp 30 and Lys 32 and suggest that these residues may be a universal determinant of sodium channel activity in these toxin families. Phe 6 , Lys 18 , Arg 26 , and Lys 27 appear to make isoform-specific interactions. These novel findings may provide a basis for the rational design of toxin-based peptides with improved VGSC potency and/or selectivity.…”

“…Fig. 7 illustrates three different views of the toxin by successive 120º rotations and highlights the close proximity of Phe 6 , Trp 30 , Lys 32 , and Tyr 33 and the deleterious effect on affinity toward both Nav1.2 and Nav1.7 when these residues are mutated to alanine (colors other than cyan indicate significant decrease in activity). These residues, along with Thr 28 , belong to ␤-strand 2, loop 1, and loop 4, creating a polar-aryl face.…”

“…2 Because the majority of spiders prey primarily on invertebrates, it is likely that these toxins target VGSCs in the insect nervous system, providing a highly efficient mechanism for spiders to incapacitate their prey. However, given the structural similarity between many insect and vertebrate sodium channels, it is not surprising that many spider venom peptides also modulate the activity of vertebrate VGSCs (5)(6)(7)(8)(9). In vertebrates, there are nine VGSC isoforms, Nav1.1-Nav1.9, with each isoform exhibiting a unique pattern of tissue distribution.…”

Discovery of a selective Na V 1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models

“…prey. In contrast to humans, insects express only a single Na V channel that is a common target of peptides in the venom of arthropod predators, such as spiders and scorpions (6). Ssm6a blocks hNav.1.7 within seconds of administration (Fig.…”

“…Humans contain nine different Na V channel subtypes, denoted Na V 1.1 to Na V 1.9 (5,6). In recent years, Na V 1.7 has emerged as a promising analgesic target based on several remarkable human genetic studies.…”